Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant’s putative impact, and predicted pathogenicity; and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462–6342 μm). Follow up after 2–11 years showed enlargement of the diameter (avg. 100 μm/year). The novel c.3457T>A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones.

Accessibility of the Shine–Dalgarno sequence dictates N-terminal codon bias in E. coli

Despite considerable efforts, no physical mechanism has been shown to explain N-terminal codon bias in prokaryotic genomes. Using a systematic study of synonymous substitutions in two endogenous E. coli genes, we show that interactions between the coding region and the upstream Shine–Dalgarno (SD) sequence modulate the efficiency of translation initiation, affecting both intracellular mRNA and protein levels due to the inherent coupling of transcription and translation in E. coli. We further demonstrate that far-downstream mutations can also modulate mRNA levels by occluding the SD sequence through the formation of non-equilibrium secondary structures. By contrast, a non-endogenous RNA polymerase that decouples transcription and translation largely alleviates the effects of synonymous substitutions on mRNA levels. Finally, a complementary statistical analysis of the E. coli genome specifically implicates avoidance of intra-molecular base-pairing with the SD sequence. Our results provide general physical insights into the coding-level features that optimize protein expression in prokaryotes.